Stereoselectivity is a concept described in the literature. Essentially it means that synthesis that produces one diastereoisomer (or diastereoisomeric dl pair) of a given structure in considerable predominance over all other possible diastereoisomers (or diastereoisomeric dl pair) of the same structure. Reference can be had to Stereochemistry of Carbon Compounds, E. L. Eliel, 1962, chapter 15, pages 434-446, McGraw-Hill, the subject matter of which is incorporated by reference herein.
A principal value of d-trans-piperitol is as an intermediate to d-isomethol by hydrogenation. d-Isomenthol is an important product since it is readily isomerized to l-menthol which in turn is an important flavoring or cooling ingredient for pharmaceuticals and other products.
The hydrogenation of d-trans-piperitol to d-isomenthol and related hydrogenation processes have been known for many years and are disclosed in the following publications:
1. "Synthesis of Laevo-menthol from a Citrus By-Product," J. C. Leffingwell and R. E. Shackelford, presented by Dr. Leffingwell at the annual Tobacco Research Chemists' Conference, Winston-Salem, North Carolina, on Oct. 5, 1973; PA1 2. "Menthol, Part 4: Manufacturing Processes and Syntheses," by Dr. Siegfried Mignat and Fredrich Porsch, Dragoco Report, 1962, No. 1, 10-23 (Page 17); PA1 3. "Reactions of Alpha, Beta-Unsaturated Cyclic Aldehydes and Ketones Part IX," A. Killen Macbeth and J. S. Shannon, Journal of the Chemical Society, 1952, 2852-2856; PA1 4. "Reactions of Alpha, Beta-Unsaturated Cyclic Aldehydes and Ketones Part XI," A. Killen Macbeth, B. Milligan and J. S. Shannon, Journal of the Chemical Society, 1953, 901-902; PA1 5. U.S. Pat. No. 3,028,418, Example No. 22 by Robert L. Webb; PA1 6. U.S. Pat. No. 2,894,040 by Joseph P. Bain et al; PA1 7. U.S. Pat. No. 2,935,526 by Joseph P. Bain.
The hydrogenation of d-trans-piperitol and such other related processes are representative of stereoselective syntheses wherein one diasteroisomer is produced in considerable predominance over other diastereoisomers. However, typically the stereoselectivity is not complete.
Although good yields of d-isomenthol are reported in the prior art, virtually all of the prior art work was carried out before vapor phase chromatograhy was available for analysis. Reported selectivities of up to 95% of d-isomenthol as determined by infrared analysis are thus open to question.
Applicants' own experience with the conventional hydrogenation of d-trans-piperitol is that it produces in addition to the desired d-isomenthol, an amount of the isomeric d-menthol,.sup.1 as shown in the following equation: ##STR1## FNT .sup.1 It has been determined that there are actually either isomers of menthol; 1-isomenthol, 1-neoisomenthol, d-menthol, 1-neomenthol, d-isomenthol, d-neoisomenthol, 1-menthol and d-neomenthol. The prefixes d- and 1- refer to optical rotatory power of each substance and do not indicate relative configurations. Thus, 1-menthol is configurationally related to d-iso, d-neo and d-neoisomenthols. The prefix "iso" means that the methyl group is in the axial position, and the prefix "neo-" means that the hydroxyl group is in an axial position (as compared to equatorial positions). A good discussion of the menthols can be found in the publication The Terpenes, Vol. 1, part 1, chapter 2, pages 230-250, by J. L. Simonsen, Cambridge at the University Press, 1947. FNT The difference between the d-isomenthol and d-menthol is in the position of the methyl group relative to the positions of the hydroxyl and isopropyl groups of the molecule. Namely, in d-isomenthol, the methyl group is in an axial position, the hydroxyl group being equatorial, whereas in d-menthol, both the methyl and hydroxyl groups are equatorial. The isopropyl group by reason of its steric size exists almost exclusively in the equatorial position.
This preferential but incomplete stereoselective hydrogenation of cyclic allylic alcohols has also been observed by S. Mitsui et al, as reported in Chemistry and Industry, Oct. 14, 1967 (1746-1747). Using 3-methylcyclohex-2-enol, they found that, over Raney nickel, hydrogen tended to attack from the same side of the double bond as the hydroxyl group.sup.2 to give stereoselectively the trans-isomer, as compared to production of more cis-isomer over a palladium catalyst. However, as indicated, the stereoselectivity was not complete, and they reported a percentage yield in the product of only 87% of the trans-isomer. FNT .sup.2 In the stereoselective synthesis of d-isomenthol, referring to the above equation, it is surmised, as in Mitsui et al, that there is a preferential attack by hydrogen from the same side of the double bond as the hydroxyl group, forcing the methyl group in the No. 1 position to form an axial bond. Some hydrogen attacks from the opposite side, however, forcing the methyl group to form an equatorial bond with the molecule.
In the above Webb U.S. Pat. No. 3,028,418, in example 22, the stereoselective hydrogenation of piperitols (in this example, d-cis-piperitol and 1-trans-piperitol to neomenthol and isomenthol, respectively) is reported. Webb gives results of 92-95% stereoselectivity, by infrared analysis, although applicants' tests conducted under similar conditions but with d-trans-piperitol, gave a product stereoselectivity of only 89.5%, as determined by vapor phase chromatography.
1-Menthol has to be of very high optical purity to meet U.S. Pharmacopoeia specifications, and the presence of d-menthol seriously lowers the optical purity of 1-menthol. In fact, the presence of d-menthol produces a racemic mixture wherein 5% d-menthol results after further processing in an optical purity of only 90% for 1-menthol. Whereas d-isomenthol is readily isomerized to 1-menthol, the d-menthol is not, and is very difficult to separate from d-isomenthol. The presence of d-menthol also has a severe effect in depressing the melting point below specification.
Thus an increase in stereoselectivity of only about 5%, to about 92%, preferably to about 95% or better, in the synthesis of d-isomenthol, is of substantial significance commercially.
A publication of interest with regard to the present invention is entitled: "Some Factors Influencing the Activity of Raney Nickel Catalyst. III. The Poisoning of Raney Nickel by Halogen Compounds," John N. Pattison and Ed. F. Degering, Journal American Chem. Soc., 73, 1951, pages 611-613. Referring in particular to FIG. 1, of the publication, it is shown that a Raney nickel catalyst has surfaces of different reactivity, and that poisoning agents, in this case HCl, react with or block the most reactive surfaces first. Specifically, the Figure shows a distinct break in the effect on hydrogenation reaction rate in the hydrogenation of styrene with additions of more than 0.005 grams HCl. Pattison et al make no mention of the effect of the poisoning on stereoselectivity, nor is the hydrogenation of allylic alcohols or the synthesis of 1-menthol mentioned in the article. The sole purpose of the article was to show the effect of catalyst poisoning with halogen compounds on reaction rates.
A similar such disclosure is contained in the publication Annalen Der Chemie, 660, (1962), pages 1-23. This publication describes the relative poisoning of Raney nickel by many compounds as determined by reduction of hydrogenation rate. No reference to stereoselectivity is contained in the publication.